This invention relates to novel compounds that are liver-selective glucocorticoid receptor antagonists and liver-selective thyroid receptor agonists, to methods of preparing such compounds, and to methods for using such compounds in the regulation of metabolism, especially lowering serum glucose and low density lipoprotein levels.
A major problem with both Type 2 and Type 1 diabetes is that there is excessive and inappropriate production of glucose by the liver. This abnormality is the primary cause of fasting hyperglycemia and occurs in addition to defects in regulation of insulin release and in peripheral sensitivity to insulin. Thus, agents that decrease liver glucose production would be beneficial for treating both Type 2 and also Type 1 diabetes.
Intensive treatment of the hyperglycemia of Type 1 diabetes mellitus has been shown markedly to decrease the development of ocular renal and neuropathic complications, and there is evidence that intensive treatment is also beneficial for Type 2 diabetes. The available data also indicate that most patients are currently not receiving ideal and state-of-the-art treatment for either Type 2 or Type 1 diabetes. This inadequacy exists in spite of the availability of several different types of preparations of insulin for treatment of both Type 2 and Type 1 diabetes, and of a number of additional modalities, including agents that stimulate insulin release (e.g., sulfonylureas), influence liver glucose production (e.g., metformin), affect the sensitivity to insulin (e.g., troglitazone) and glucose absorption (e.g., xcex1-glucosidase inhibitors). In spite of the availability of several different orally-active agents that lower blood glucose levels. many patients with Type 2 diabetes also require insulin for control of their blood sugar levels. Overall, insulin usage in Type 2 diabetes exceeds that for Type 1 diabetes, and there is general agreement that there is a need for additional orally-active agents to treat Type 2 diabetes.
The glucocorticoid secretions of the adrenal gland (dominantly cortisol in humans) were so named because of their ability to regulate glucose metabolism. These steroids stimulate the production of glucose in the liver by promoting gluconeogenesis, which is the biosynthesis of new glucose (i.e. not glucose from glycogen). Thus, in glucocorticoid insufficiency there is a tendency to hypoglycemia, with decreased liver glucose production. Further development of Addison""s disease in the diabetic patient generally leads to lowered glucose levels. Conversely, glucocorticoid excess can provoke frank diabetes in individuals with latent diabetes mellitus, and generally aggravates glycemic control in established diabetic patients. Similar influences have been observed in various animal models.
The increased glucose production in response to glucocorticoids is due to effects on a number of proteins. Important among these are effects on various transaminases that convert amino acids to glucose precursors, and induction of glucose-6 phosphatase and phosphoenolpyruvate carboxy-kinase (PEPCK). Even a modest increase of PEPCK, as obtained in transgenic mice, gives rise to hyperglycemia. In mice with Type 2 diabetes and increased levels of corticosterone (the endogenous glucocorticoid of that species) there is increased expression of PEPCK. This over expression of PEPCK can be repressed by treatment with the known GR antagonist RU486 with a concomitant decrease in the hyperglycemia.
The considerations outlined above indicate that if the action of endogenous glucocorticoids on liver glucose production could be blocked in a specific manner, glycemic control could be improved for the benefit of the diabetic patients. However, to date, all means to block glucocorticoid action have been general. Thus, adrenalectomy leaves the patient with frank adrenal insufficiency and the problems of Addison""s disease. Blockade of adrenal steroid production, for example by metyrapone, or of glucocorticoid action, for example with RU486, is ordinarily of limited duration of effectiveness and when it is effective also results in generalized adrenal insufficiency. Long term compensatory ACTH hypersecretion and increased cortisol release that override the block generally overcome these treatments. By contrast, a liver-specific GR antagonist would not have these problems, should counteract the increased liver glucose production in diabetes mellitus, and should be useful for treatment of Type 2 diabetes.
A liver selective GR antagonist offers a number of advantages. First, it should decrease liver glucose production. This action will have a significant effect on glycemic control. In fact, excessive liver glucose production can be the major defect in Type 2 diabetes. Secondly, such a drug should enhance insulin sensitivity because of the overall improvement in the metabolic milieu and the amelioration of the hyperglycemia-induced defects in insulin action and secretion. The decreased demand on xcex2-cell secretion, as a result of a reduction in glycemia, would retard the progressive xcex2-cell dysfunction characteristic of Type 2 diabetes. Another advantage of GR antagonist treatment compared with sulfonylurea or insulin treatment is that the patient would run a lower risk of hypoglycemia.
Previous efforts to block glucocorticoid action in diabetes have been hampered by the fact that any compounds used would generally block glucocorticoid action in all tissues and would lead to the potential problems of glucocorticoid insufficiency, such as hypotension, shock, and ultimately death if the organism were exposed to sufficiently-strong stress conditions. In contrast, a liver-selective GR-antagonist with minimal effects outside the liver could be used as a front-line therapy for Type 2 diabetes, or could be used in conjunction with other existing therapies.
Thyroid hormones affect the metabolism of virtually every cell of the body. At normal levels. these hormones maintain body weight, the metabolic rate, body temperature, and mood, and influence serum low density lipoprotein (LDL) levels. Thus, in hypothyroidism there is weight gain, high levels of LDL cholesterol, and depression. In excess with hyperthyroidism, these hormones lead to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmias, heart failure, muscle weakness, bone loss in postmenopausal women, and anxiety.
Thyroid hormones are currently used primarily as replacement therapy for patients with hypothyroidism. Therapy with L-thyroxine returns metabolic functions to normal and can easily be monitored with routine serum measurements of levels of thyroid-stimulating hormone (TSH), thyroxine (3,5,3xe2x80x2, 5xe2x80x2-tetraiodo-L-thyronine, or T4) and triiodothyronine (3,5,3xe2x80x2-triiodo-L-thyronine, or T3). However, certain of the deleterious effects of thyroid hormones limit the rapidity with which replacement therapy can be given and in some circumstances, particularly in older individuals, even completely exclude replacement therapy.
In addition, some effects of thyroid hormones may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated. These potentially-useful influences include weight reduction, lowering of serum LDL levels, amelioration of depression and stimulation of bone formation. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism, and in particular by cardiovascular toxicity.
Development of liver specific and selective thyroid hormone receptor agonists could lead to specific therapies for lowering of serum LDL levels while avoiding the cardiovascular and other toxicities of native thyroid hormones. Tissue-selective thyroid hormone agonist may be obtained by selective tissue uptake or extrusion, topical or local delivery, targeting to cells through other ligands attached to the agonist.
In accordance with the present invention, compounds are provided which are glucocorticoid and thyroid hormone receptor ligands, and have the general formula I: 
in which:
R1 is an aliphatic hydrocarbon, an aromatic hydrocarbon, a carboxylic acid or ester thereof, alkenyl carboxylic acid or ester thereof, hydroxy, halogen, or cyano, or a pharmaceutically salt thereof, and all stereoisomers thereof;
R2 and R3 are the same or different and are hydrogen, halogen, alkyl of 1 to 4 carbons or cycloalkyl of 3 to 6 carbons, at and least one of R2 and R3 being other than hydrogen.
X is carbonyl (Cxe2x95x90O) or methylene (CH2).
R4 is an aliphatic, other than C1 aromatic, heteroaromatic or cycloaliphatic group
R5 is hydrogen, halogen, alkyl of 1 to 4 carbons, cycloalkyl of 3 to 6 carbons or cycloalkyl alkyl of 5 to 8 carbons.
Y is hydroxyl, methoxy, amino, alkyl amino or amide.
Preferably, L is a linear or branched C2 to C6 alkyl more preferably t-butyl.
R2 and R3 are preferably halogen or a halogenated alkyl, more preferably bromine or another hydrophobic group of similar size to bromine. A possible halogenated alkyl is xe2x80x94CF3.
In the (CH2 )n R1 side chain n is preferably 1.
R1 is an acidic or negatively-charged group, and
carboxylic acid or a bioisoster of carboxylic acid is preferred. Bioisosters of carboxylic acids are groups that display the same receptor-binding activity and thus, in general. the same in vivo activity. Examples are tetrazole, acylsulphonamides, phosphonates, and sulphonates.
In addition, in accordance with the present invention, a method for preventing, inhibiting, or treating a disease associated with a metabolic dysfunction or which is dependent upon the expression of a glucocorticoid or thyroid hormone receptor regulated gene is provided, wherein a compound of formula I is administered in a therapeutically effective amount. The compound of formula I is preferably also liver selective. Examples of such diseases associated with metabolic dysfunctions or are dependent upon the expression of a glucocorticoid receptor regulated gene are set out hereinafter and include diabetes and inflammation. Examples of such diseases that are dependent upon expression of thyroid hormone receptor regulated gene include obesity, hypercholoesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goitre, thyroid cancer as well as glaucoma and congestive heart failure.
The following definitions apply to the terms as used throughout this specifications. unless otherwise limited in specific instances.
The term xe2x80x9cglucocorticoid receptor ligandxe2x80x9d as used herein is intended to cover any moiety that binds to a glucocorticoid receptor. The term xe2x80x9cthyroid hormone receptor ligandxe2x80x9d as used herein is intended to cover any moiety that binds to a thyroid hormone receptor. The ligand may act as an agonist, an antagonist, a partial agonist, or a partial antagonist.
The term xe2x80x9caliphatic hydrocarbon(s) as used herein refers to acyclic straight or branched chain groups which include alkyl, alkenyl, or alkynyl groups.
The term xe2x80x9caromaticxe2x80x9d hydrocarbons(s) as used herein refers to groups including aryl groups as defined herein.
The term xe2x80x9carylxe2x80x9d as employed herein alone or as part of another group refers to monocylcic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or napthyl including 1-naphthyl and 2-naphthyl) and may be optionally substituted through available carbon atoms with 1, 2, or 3 groups selected from hydrogen, halo, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, trifluoromethyl, thiomethyl, difluoromethyloxy trifluoromethyloxy, thiotrifluoromethyl, alkynyl, hydroxy, nitro, or cyano.
Unless otherwise indicated, the term xe2x80x9clower alkenylxe2x80x9d or xe2x80x9calkenylxe2x80x9d as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 12 carbons, preferably 2 to 5 carbons, in the normal chain, which include one to six double bonds in the normal chain, such as vinyl, 2-propenyl, 3-butenyl, 2-butenyl, 4-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 3-octenyl, 3-nonenyl, 4-decenyl, 3-undecenyl, 4-dodecenyl, and the like.
Unless otherwise indicated, the term xe2x80x9clower alkynylxe2x80x9d or xe2x80x9calkynylxe2x80x9d as used herein by itself or as part of another group refers to straight or branched chain radicals of 2 to 12 carbons, preferably 2 to 8 carbons, in the normal chain, which include one triple bond in the normal chain, such as 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl, 2-heptynyl, 3-heptynyl, 4heptynyl, 3-octynyl, 3-nonynyl, 4-decynyl, 3-undecynyl, 4-dodecynyl and the like.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine as well as CF3, with chlorine or bromine being preferred.
The term xe2x80x9caminoxe2x80x9d as employed herein alone or as part of another group may optionally be independently substituted with one or two substituents, which may be the same or different, such as alkyl, aryl, arylalkyl, hydroxyaryl, heteroaryl, heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl or thioalkyl. These substituents may be further substituted with a carboxylic acid or any of the substituents for alkyl as set out above. In addition, the amino substituents may be taken together with the nitrogen atom to which they are attached to form 1pyrrolidinyl, 1piperidinyl, 1azepinyl, 4morpholinyl, 4thiamorpholinyl, 1piperazinyl, 4alkyl1piperazinyl, 4arylalkyl1piperazinyl, 4diarylalkyl1piperazinyl, 1pyrrolidinyl, 1piperidinyl, or 1azepinyl, optionally substituted with alkyl, alkoxy, alkylthio, halo, trifluoromethyl or hydroxy.
The compounds of formula I can be present as salts, in particular pharmaceutically acceptable salts. If the compounds of formula I have, for example, at least one basic center, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C1-C4)alkyl or arylsulfonic acids which are unsubstituted or substituted, for example by halogen, for example methane- or ptoluene-sulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds of formula I having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or trilower alkylamine, for example ethyl, tertbutyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono di or triethanolamine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds I or their pharmaceutically acceptable salts, are also included.
Preferred salts of the compounds of formula I which include a basic group include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate or nitrate.
Preferred salts of the compounds of formula I which include an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.
Preferred are compounds of the invention of formula I wherein:
R1 is carboxylic acid (COOH) or esters thereof, OH, CN, or halogen.
R2 and R3 are halogen such as bromo or chloro; or
R2 and R3 are each isopropyl or one is isopropyl and the other is ethyl or tert-butyl.
R4 is aryl.
R5 is isopropyl.
X is a carbonyl (Cxe2x95x90O) or methylene (CH2).
Y is hydroxyl or methoxy.
n is 0-4.
Especially preferred compounds of the invention have the structures 
The compounds of formula I may be prepared by the processes exemplified in the following reaction schemes. Examples of reagents and procedures for these reactions appear hereinafter and in the working Examples.
Compounds of formula I of the invention can be prepared using the sequence of steps outlined in Scheme 1 or 2 set out below. 
The compounds of the invention are glucocorticoid receptor antagonists or thyroid receptor agonists that are preferably liver selective, and as such are useful in the treatment of diabetes (alone or in combination with agents that stimulate insulin release such as sulfonylureas, influence liver glucose production such as metformin, affect the sensitivity to insulin such as troglitazone, or inhibit glucose absorption such as xcex2-glucosidase inhibitors), obesity, hypercholesterolemia and atherosclerosis by lowering of serum LDL levels (alone or in combination with a cholesterol-lowering drug such as an HMG CoA reductase inhibitor).
The compounds of the invention can be administered orally or parenterally such as subcutaneously or intravenously, as well as by nasal application, rectally or sublingually to various mammalian species known to be subject to such maladies, e.g., humans, cats, dogs and the like in an effective amount within the dosage range of about 0.1 to about 100 mg/kg, preferably about 0.2 to about 50 mg/kg and more preferably about 0.5 to about 25 mg/kg (or from about 1 to about 2500 mg, preferably from about 5 to about 2000 mg) on a regimen in single or 2 to 4 divided daily doses.
The active substance can be utilized in a composition such as tablet, capsule, solution or suspension or in other type carrier materials such as transdermal devices, iontophoretic devices, rectal suppositories, inhalant devices and the like. Pharmaceutical compositions of this invention comprise any of the compounds of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
The pharmaceutical compositions of this invention may be dministered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. The term parenteral as used herein includes subcutaneous, intracutaneous, intrave-nous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injec-tion or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspen-sion may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the ac-ceptable vehicles and solvents that may be employed are mannitol, water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conven-tionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharma-ceutical-ly-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Helv or a similar alcohol.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspen-sions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stea-rate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsify-ing and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combina-tion, the severity and course of the disease, the patient""s disposition to the disease and the judgment of the treating physician. The composition or carrier will contain about 5 to about 500 mg per unit of dosage of a compound of formula I. They may be compounded in conventional matter with a physiologically-acceptable vehicle or carrier, excipient, binder, preservative, stabilizer, flavor, etc., as called for by accepted pharmaceutical practice.